Intracellular enteric infections are a global problem resulting in millions of hospitalizations and deaths every year. CD8 T cells are potent cytotoxic cells that control intracellular infection, and as such, represent a potential population to targetfor therapeutics and vaccine development. With this in mind, considerable characterizations, encompassing many aspects of CD8 T cell immunobiology, have resulted in substantial increases in our general understanding of CD8 T cell function. Up until recently, the paradigm for memory CD8 T cell function upon pathogen challenge centered on the hypothesis that memory CD8 T cell responses were predominantly generated within secondary lymphoid tissue. However, newer reports have highlighted important functions of memory CD8 T cells outside of secondary lymphoid tissue. For instance, it has recently been shown that memory CD8 T cells within nonlymphoid tissues provide important and potent early responses to local pathogen challenge. The mechanism by which this occurs is still not entirely understood, nor is it known how these responses are related to ones generated by CD8 T cells outside of the infected tissue. Moving forward, it will be critical to understand whether these responses within infected tissues operate in cooperative versus parallel manners with CD8 T cells outside of the infected site. The central hypothesis of this proposal is that there exist multiple populations of memory CD8 T cells outside of tissues that differentially migrate into the small intestine under homeostatic conditions and during states of inflammation. Further, these memory CD8 T cells may provide an important, early wave of cytotoxic responses within the small intestine. Therefore, my specific aims will 1) determine the functionality and importance of these different populations in response to pathogen challenge; 2) determine the stability and trafficking patterns of these different populations of CD8 T cell memory. This proposal supports the mission of the NIDDK because it focuses understanding memory CD8 T cell responses to intracellular gastrointestinal infections. With a better understanding of memory CD8 T cell function in the small intestine, could provide important information for rational vaccine design targeting CD8 T cells.